Mutations in the gene encoding the microtubule associated protein tau can lead to devastating neurodegenerative diseases in humans. Previous studies in humans and mice have shown that synapse loss is one of the earliest events in tau-mediated neurodegeneration. Until recently however, it has been impossible to assess the effects of this synapse loss on the function of cells and circuits in the intact brain. The studies put forward in this proposal will: 1) determine how mutant tau expression affects the spontaneous and evoked activity of neurons within the mouse cerebral cortex, 2) characterize the consequences of mutant tau expression on cortical information processing, and 3) assess the dysfunction of local cortical circuits caused by mutant tau. These studies will use in vivo two-photon imaging with calcium indicators to determine how synaptic defects lead to cellular and system-wide dysfunction in mouse models of tau-mediated disease. I anticipate that these studies will improve the current understanding of the initiating events of neurodegeneration and how neural activity is compromised in brains expressing mutant forms of tau. PUBLIC HEALTH RELEVANCE: A tremendous gap in our understanding of neurodegenerative diseases lies between the molecular events that occur at the synapse and the cognitive decline of people suffering from these devastating diseases. The dysfunction of the neuronal protein tau is a hallmark of many neurodegenerative diseases such as Alzheimer's Disease, Pick's Disease and Frontotemporal Dementia, and is known to disrupt synaptic signaling and lead to cognitive decline. This proposal aims to bridge the gap in our understanding by determining the effects of mutant tau on neuronal activity and neural circuit function by using the powerful tools of transgenic mouse models of disease and in vivo two-photon imaging of activity within the living brain.